The present invention relates to novel thioester derivatives of thiazolyl acetic acid of the general formula (I), useful as an intermediate for the preparation of cephalosporin antibiotics having the general formula (II). In addition, the present invention also relates to a process for preparation of cephalosporin antibiotics using the said thioester derivatives. 
Wherein, R1 represents H, trityl, CH3, CRaRbCOOR2 (Ra and Rb independently of one another represent hydrogen or methyl and R2 represents H or C1-C4 alkyl).
Use of acid chlorides, anhydrides, esters, amide etc. are reported in the chemical literature for activation of carboxylic acid of formula (IV). Activation in the form 
of acid chloride required protection and deprotection of NH2 group.
Activation of acid (IV) is reported by SO2Cl2/DMF in U.S. Pat. No. 5,856,502 and SOCl2/DMF in U.S. Pat. No. 5,037,988. These processes suffer the limitation of using harmful and pungent smelling chemicals like SOCl2, SO2Cl2 along with solvents like benzene, toluene, etc. and involving stringent conditions for carrying out the reactions at commercial scale.
In U.S. Pat. Nos. 4,576,749 and 4,548,748, the acid of formula (IV) has also been activated by reacting with 1-hydroxybenzotriazole (HOBT) or 2-mercaptobenzothiazole (MBT) in the presence of dicyclohexylcarbodiimide (DCC) to produce reactive ester of the acid (IV) which is then reacted with cephem moiety to prepare cephalosporin antibiotics, but the processes are time consuming accompanied with low yields, hence, not suitable.
U.S. Pat. No. 4,767,852 discloses a process for production of cephems by acylating 7-amino-3-cephem-4-carboxylic acid with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate (MAEM). Similarly, U.S. Pat. No. 5,026,843 (1991) disclosed a process for preparing ceftriaxone disodium hemiheptahydrate by acylation of 7-amino-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3yl) thiomethyl]-3-cephem-4-carboxylic acid (7-ACT) by using MAEM as acylating agents in good yield and quality. Thus MAEM has become the standard acylating agent for the preparation of cephalosporins antibiotics having an oximino group and a 2-aminothiazolyl group in 7-position of cephem compounds.
However, the synthesis of MAEM from acid (III) and 2,2xe2x80x2-dithio-bis-benzothiazole involves use of costly condensing agent triphenylphosphine (TPP). Moreover, during condensation of MAEM with 7-amino-3-cephem-4-carboxylic acid compound (III), a toxic compound 2-mercaptobenzothiazole (MBT) is also produced as a byproduct [Chemical Abstracts, 111, p.19243 (1989)], which is difficult to remove.
Thus, it is evident that the procedures described in the prior art for the preparation of these cephalosporin antibiotics are complex, involving protection, deprotection and also associated with generation of toxic byproduct. Hence, there is a need to develop new acylating agents which are capable of transferring the 2-aminothiazolyl moiety to cephem compounds of formula (III) in good yield, without producing this toxic byproduct. On the similar lines, a new thioester was reported by D. G. Walker, Tet. Lett. 1990, 31,6481 to acylate the cephem moiety to get cefepime sulfate but yields obtained by using this thioester were in the range of 54-73% which cannot be considered as good yield to operate a process at commercial scale. The same thioester is exploited in U.S. Pat. No. 5,869,649 for making three more important cephalosporin antibiotics.
In the co pending application U.S. application Ser. No. 09/754,302, U.S. Pat. No. 6,388,070 the Applicant has disclosed another novel thioester derivative of thiazole acetic acid and its use in the synthesis of various ceplalosporin antibiotics. In continuation of search for more such derivatives, the Applicant observed that the title compound (I) works equally well and also has the similar advantages as described in the aforementioned US application.
The primary objective of this invention is to prepare a new thioester derivative of thiazolyl acetic acid of the formula (I), which would be better than the earlier reactive derivatives and also suitable for being used in the manufacture of cephalosporin antibiotics.
Another objective of the present invention is to provide a process for the synthesis of thioester derivative of formula (I) from thiazolyl acetic acid of the formula (IV) and 1,2,5,6 tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-thiol (VI).
Yet another objective of the present invention is to provide a process for the preparation of cephalosporin antibiotics of the general formula (II) at low temperature, which will be simple and cost effective.
Still another objective of the present invention is to produce cephalosporin antibiotics that are high purity and free from toxic byproducts.
One more objective of the present invention is to provide a process for the preparation of cephalosporin antibiotics of the general formula (II) from the said novel thioester derivatives.
The present invention provides a new thioester derivatives of thiazolyl acetic acid of formula (I) and also provides a method by which the said thioester derivatives can be prepared by reacting thiazolyl acetic acid of the general formula (IV) with the commercially available 1,2,5,6 tetrahydro-2-methyl-5,6 dioxo-1,2,4-triazin-3-thiol (VI) using Vilsmeier reagent (V) as a condensing agent. (Ber. 60B, 119 (1927). The thioester derivatives thus obtained are reacted with 7-amino-cephem carboxylic acids of the general formula (III) to produce cephalosporin antibiotic compounds of the general formula (II), as described above. The cephalosporin antibiotics obtained are of high purity (95-99%). The method is workable at commercial scale without necessitating for the protection of the amino group of the acylating agents, and avoiding the generation of the toxic byproduct 2-mercaptobenzothiazole.
1. The present invention provides a process for the preparation of a new thioester of the formula (I), as mentioned earlier. The said process comprises condensation of thiazolylacetic acid represented by formula (IV) 
wherein, R1 represents H, trityl, CH3, CRaRbCOOR2 (Ra and Rb independently of one another represents hydrogen or methyl and R2 represents H or C1-C4 alkyl).
with 1,2,5,6 tetrahdro-2-methyl-5,6 dioxo-1,2,4-triazin-3-thiol of formula (VI) 
In presence of Vilsmeier reagent of the formula (V) in an organic solvent. 
at temperature being maintained in the range xe2x88x9210xc2x0 C. to +30xc2x0 C.
The thioester of general Formula (I) thus obtained is reacted with 7-amino cephem carboxylic acids of the general formula (III) in organic solvent in presence of organic base to obtain cephalosporin antibiotics of the general formula (II). 
wherein, in formula (I), R1 represents H, trityl, CH3, CRaRbCOOR2 (Ra and Rb independently of one another represents hydrogen or methyl and R2 represents H or C1-C4 alkyl).
In formula (III) R3 represents CH3, xe2x80x94CHxe2x95x90CH2, CH2OCH3, CH2OCOCH3, 
R4 is hydrogen, salt, carboxylic protecting group or an inner salt.
R5 is hydrogen or trialkylsilyl.
wherein formula (II), R1, R3 and R4 are as defined above.
Another embodiment of the present invention provides a method by which cephalosporin antibiotics are obtained in high purity and excellent yield without the necessity for protecting the amino group of the acylating agents and avoiding the production of toxic byproduct namely 2-mercaptobenzothiazole(MBT).
In one another embodiment of the present invention, the substituent R3 in cephem compound (II) and (III) represents methyl, acetyloxymethyl, methoxymethyl, vinyl, pyridylmethyl, propenyl, 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazine-3-thiol, furanyl-2-carbonylthiol. In general, R3 represents xe2x80x94CH2xe2x80x94X wherein X is a residue of any organic or inorganic nucleophilic compound, e.g., halogen, hydroxy, cyano, mercapto, azido, amino, etc. Furthermore, X may preferably represent residue of any 5 or 6 membered heterocyclic thiol.
In yet another embodiment of the present invention, the substituent R4 represents hydrogen, salt, a standard carboxylic protecting group, or a inner salt. Especially it is termed as carboxylate ion when R3 is pyridylmethyl, which ultimately explains the neutrality of the molecules.
Another embodiment of the invention provides the use of Vilsmeier reagent of formula (V) as condensing agent.
Still another embodiment of the invention provides acylation of (III) (when R5 is H) is performed in presence of a water miscible solvent like tetrahydrofuran (THF), acetonitrile, acetone, dioxane, N,N-dimethylformamide etc. but the preferable solvents are THF and acetonitrile.
In an embodiment of the present invention, acylation of (III) (when R5 is trimethylsilyl) is carried out in aprotic organic solvents like halogenated hydrocarbons, toluene, acetonitrile, alkyl ethers etc., but preferable solvent is acetonitrile and dichloromethane. More suitable silylating agents used for the reaction are hexamethyldisalazane, bis(trimethyl)silylacetamide and trimethylsilyl chloride or a mixture thereof.
In yet another embodiment of the present invention, the organic base may be selected from triethylamine, diethylamine, tributylamine, N-alkylpipridine, N-alkylanilines, 1,8-diazabicyclo[5.4.2]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, N-methylmorpholine, 1,4-diazabicyclo[2.2.2]octane, 4-dimethylamino pyridine and mixtures thereof.
The conceptual utility of this new thioesters of 1,2,5,6 tetrahdro-2-methyl-5,6 dioxo-1,2,4-triazin-3-thiol of the general formula (VI) is also tried in various coupling reactions of carboxylic acids and amines. Most of amide formation reactions have shown good results. L-alanine, 5-methylisoxazole-4-carboxylic acid, 2-thienylacetic acid, etc. are some of the compounds, which have been activated by above mentioned thiol of formula (VI). Some of the results are summarized in the following table.
Many other beneficial results are obtained by applying disclosed invention in a different manner or by modifying the invention with the scope of disclosure. However, since the major characteristic feature of the present invention resides in the use of novel reactive thioester derivatives of thiazolyl acetic acid of the general formula (I) in preparing the cephalosporin antibiotics, the technical scope of the present invention should not be limited to the following examples.